In recent years the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) have emphasized a desire to see greater control and process understanding in the area of pharmaceutical development, manufacturing and quality assurance which is collectively referred to as process analytical technology (PAT). Likewise, bioprocessing and specifically cell culture application users are interested in attaining more advanced, informative and significant real-time data out of their systems to drive process development and manufacturing success while also ushering in a generation of advanced process control (APC).
While the real-time monitoring of pH, dissolved oxygen (DO), dissolved CO2 and temperature are relevant to cell culture applications and have been typical online monitoring and control parameters within cell culture and bioprocessing applications for decades, there are also other process parameters that involve manual bioreactor sampling and offline analysis. These parameters may include total cell density (TCD) and, viable cell density (TCD), protein production and cell metabolism components including amino acids, growth nutrients, and cell waste products. A need exists to transfer the monitoring of these traditionally offline measured parameters towards an in situ application which will create the potential for real-time control. Driving this transition to PAT and APC while also meeting the guidance provided in the regulatory framework poses specific challenges for the development, manufacturing and quality assurance of biologics due to the multivariate nature of the environments required for synthesizing these complex protein structures.